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Tafinlar

"The U.S. Food and Drug Administration today approved two new drugs, Tafinlar (dabrafenib) and Mekinist (trametinib), for patients with advanced (metastatic) or unresectable (cannot be removed by surgery) melanoma, the most dangerous type of skin "...

Tafinlar

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in another section of the label:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the WARNINGS AND PRECAUTIONS section and below reflect exposure to TAFINLAR as a single agent and in combination with trametinib.

BRAF V600E Unresectable or Metastatic Melanoma

The safety of TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg).

Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of Trial 1 [see Clinical Studies]. Trial 1, a multicenter, international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/m² intravenously every 3 weeks (n = 63). The trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology ( ≥ Grade 2), corrected QT interval ≥ 480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate dehydrogenase deficiency. The median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients. The population exposed to TAFINLAR was 60% male, 99% white, and had a median age of 53 years.

The most commonly occurring adverse reactions ( ≥ 20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The most frequent ( ≥ 2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%).16

Table 3: Selected Common Adverse Reactions Occurring in ≥ 10% (All Grades) or ≥ 2% (Grades 3 or 4) of Patients Treated With TAFINLARa

Primary System Organ Class Preferred Term TAFINLAR
N = 187
Dacarbazine
N = 59
All Grades (%) Grades 3 and 4b (%) All Grades (%) Grades 3 and 4 (%)
Skin and subcutaneous tissue disorders
  Hyperkeratosis 37 1 0 0
  Alopecia 22 NAf 2 NAf
  Palmar-plantar erythrodysesthesia syndrome 20 2 2 0
  Rash 17 0 0 0
Nervous system disorders
  Headache 32 0 8 0
General disorders and administration site conditions
  Pyrexia 28 3 10 0
Musculoskeletal and connective tissue disorders
  Arthralgia 27 1 2 0
  Back pain 12 3 7 0
  Myalgia 11 0 0 0
Neoplasms benign, malignant, and unspecified (including cysts and polyps)
  Papillomac 27 0 2 0
  cuSCCd, e 7 4 0 0
Respiratory, thoracic, and mediastinal disorders
  Cough 12 0 5 0
Gastrointestinal disorders
  Constipation 11 2 14 0
Infections and infestations
  Nasopharyngitis 10 0 3 0
a Adverse drug reactions, reported using MedDRA and graded using CTCAE version 4.0 for assessment of toxicity.
b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1).
c Includes skin papilloma and papilloma.
d Includes squamous cell carcinoma of the skin and keratoacanthoma.
e Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.
f NA = not applicable.

Table 4: Incidence of Laboratory Abnormalities Increased From Baseline Occurring at a Higher Incidence in Patients Treated With TAFINLAR in Trial 1 [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)]

Test TAFINLAR
N = 187
DTIC
N = 59
All Grades (%) Grades 3 and 4 (%) Grades (%) Grades 3 and 4 (%)
Hyperglycemia 50 6 43 0
Hypophosphatemia 37 6a 14 2
Increased alkaline phosphatase 19 0 14 2
Hyponatremia 8 2 3 0
a Grade 4 laboratory abnormality limited to hypophosphatemia (n = 1).

Other clinically important adverse reactions observed in < 10% of patients (N = 586) treated with TAFINLAR were:

Gastrointestinal Disorders: Pancreatitis.

Immune System Disorders: Hypersensitivity manifesting as bullous rash.

Renal and Urinary Disorders: Interstitial nephritis.

BRAF V600E or V600K Unresectable or Metastatic Melanoma

The safety of TAFINLAR in combination with trametinib was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to trametinib for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to trametinib for greater than one year. The median age was 54 years, 57% were male, and > 99% were white.

Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg twice daily in combination with trametinib 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with trametinib 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and trametinib (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and trametinib (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.

In Trial 2, 13% of patients receiving TAFINLAR in combination with trametinib experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with trametinib. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and trametinib when used in combination.19

Table 5: Common Adverse Drug Reactions Occurring in ≥ 10% at (All Grades) or ≥ 5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With Trametinib in Trial 2

Adverse Reactions TAFINLAR plus Trametinib 2 mg
N = 55
TAFINLAR plus Trametinib 1 mg
N = 54
TAFINLAR
N = 53
All Gradesa Grades 3 and 4 All Gradesa Grades 3 and 4 All Gradesa Grades 3 and 4
General disorders and administrative site conditions
  Pyrexia 71 5 69 9 26 0
  Chills 58 2 50 2 17 0
  Fatigue 53 4 57 2 40 6
  Edema peripheralb 31 0 28 0 17 0
Skin and subcutaneous tissue disorders
  Rashc 45 0 43 2 53 0
  Night Sweats 24 0 15 0 6 0
  Dry skin 18 0 9 0 6 0
  Dermatitis acneiform 16 0 11 0 4 0
  Actinic keratosis 15 0 7 0 9 0
  Erythema 15 0 6 0 2 0
  Pruritus 11 0 11 0 13 0
Gastrointestinal disorders
  Nausea 44 2 46 6 21 0
  Vomiting 40 2 43 4 15 0
  Diarrhea 36 2 26 0 28 0
  Abdominal paind 33 2 24 2 21 2
  Constipation 22 0 17 2 11 0
  Dry mouth 11 0 11 0 6 0
Nervous system disorders
  Headache 29 0 37 2 28 0
  Dizziness 16 0 13 0 9 0
Respiratory, thoracic, and mediastinal disorders
  Cough 29 0 11 0 21 0
  Oropharyngeal pain 13 0 7 0 0 0
Musculoskeletal, connective tissue, and bone disorders
  Arthralgia 27 0 44 0 34 0
  Myalgia 22 2 24 0 23 2
  Back pain 18 5 11 0 11 2
  Muscle spasms 16 0 2 0 4 0
  Pain in extremity 16 0 11 2 19 0
Metabolism and nutritional disorders
  Decreased appetite 22 0 30 0 19 0
  Dehydration 11 0 6 2 2 0
Psychiatric Disorders
  Insomnia 18 0 11 0 8 2
Vascular disorders
  Hemorrhagee 16 5 11 0 2 0
Infections and infestations
  Urinary tract infection 13 2 6 0 9 2
Renal and urinary disorders
  Renal failuref 7 7 2 0 0 0
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.
b Includes the following terms: peripheral edema, edema, and lymphedema.
c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular.
d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage.
f Includes the following terms: renal failure and renal failure acute.

Other clinically important adverse reactions (N = 202) observed in < 10% of patients treated with TAFINLAR in combination with trametinib were:

Eye Disorders: Vision blurred, transient blindness.

Gastrointestinal Disorders: Stomatitis, pancreatitis.

General Disorders and Administration Site Conditions: Asthenia.

Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.

Vascular Disorders: Hypertension.

Table 6: Treatment-Emergent Laboratory Abnormalities Occurring at ≥ 10% (All Grades) or ≥ 2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With Trametinib in Trial 2

Tests TAFINLAR plus Trametinib 2 mg
N = 55
TAFINLAR plus Trametinib 1 mg
N = 54
TAFINLAR
N = 53
All Grades Grades 3 and 4 All Grades Grades 3 and 4 All Grades Grades 3 and 4a
Hematology
  Leukopenia 62 5 46 4 21 0
  Lymphopenia 55 22 59 19 40 6
  Neutropenia 55 13 37 2 9 2
  Anemia 55 4 46 7 28 0
  Thrombocytopenia 31 4 31 2 8 0
Liver Function Tests
  Increased AST 60 5 54 0 15 0
  Increased alkaline phosphatase 60 2 67 6 26 2
  Increased ALT 42 4 35 4 11 0
  Hyperbilirubinemia 15 0 7 4 0 0
Chemistry
  Hyperglycemia 58 5 67 6 49 2
  Increased GGT 56 11 54 17 38 2
  Hyponatremia 55 11 48 15 36 2
  Hypoalbuminemia 53 0 43 2 23 0
  Hypophosphatemia 47 5 41 11 40 0
  Hypokalemia 29 2 15 2 23 6
  Increased creatinine 24 5 20 2 9 0
  Hypomagnesemia 18 2 2 0 6 0
  Hyperkalemia 18 0 22 0 15 4
  Hypercalcemia 15 0 19 2 4 0
  Hypocalcemia 13 0 20 0 9 0
a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent.
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.22

QT Prolongation: In Trial 2, QTcF prolongation to > 500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with trametinib and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with trametinib and 2% (1/53) of patients treated with TAFINLAR as a single agent.

Read the Tafinlar (dabrafenib capsules) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Effects Of Other Drugs On Dabrafenib

Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see CLINICAL PHARMACOLOGY]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

Effects Of Dabrafenib On Other Drugs

Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see CLINICAL PHARMACOLOGY]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

Trametinib

Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 1/22/2014
This monograph has been modified to include the generic and brand name in many instances.

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